Sickle cell disease (SCD) is rapidly emerging as a public health issue globally. It is an inherited blood disorder that occurs predominantly in individuals of African descent; it affects about 100,000 individuals in the USA with one in 365 black children in the US born with SCD. A characteristic feature of SCD is the extremely variable disease severity which presents major challenges in clinical management. With improved general medical care and increased life span, the disparate clinical outcome will become more apparent with increasingly variable emerging complications affecting kidneys, brain, liver, heart and lungs. Bone marrow transplantation remains the only cure but it is a high-risk procedure, appropriate for a minority of patients and often performed too late after a major complication, such as stroke, has occurred. It is clear that the genetic background and co-inheritance of other genes have a great influence on the severity of SCD. For example, studies have shown that patients who can produce high levels of fetal hemoglobin (HbF) have a milder disease and a lower risk of stroke. The brain is a major site of morbidity in children with SCD, overt stroke affects about 6% of ten year olds, with the highest stroke incidence in 2 year olds. Early cerebrovascular disease can be detected by Transcranial Doppler (TCD) scanning demonstrating increased blood velocity in the middle cerebral artery and studies have shown that starting blood transfusions at this stage can prevent progressive vasculopathy and stroke. However some children are transfused unnecessarily as 40% are predicted to remain stroke-free without transfusion 10 years after abnormal TCD, and others develop stroke despite a normal TCD scan. Further, a recent study suggested that some children, despite receiving regular blood transfusion therapy for secondary stroke prevention, continue to experience cerebrovascular damage. Ideally, one would like to identify children at high risk of cerebrovascular disease before the TCD becomes abnormal, because at that stage damage has already occurred. In addition to overt stroke, silent brain infarcts affect up to 20% of children with SCD in whom there has been no clear history of stroke but brain MRI shows small infarcts. These silent infarcts also start to occur in the first few years of life, and are associated with cognitive impairment and poor school performance. They cannot easily be detected without brain MRI which is difficult to perform routinely in young children because of the need for general anesthesia. An unmet healthcare need in SCD is the ability to predict disease severity to facilitate early intervention thereby minimizing organ damage and improving patient quality of life. Currently, there are two established genetic modifiers fetal hemoglobin (HbF) levels and co-inheritance of alpha thalassemia but these 2 genetic variants do not explain all the variability in the disease spectrum. Identification of other genetic variants may also allow prediction of other complications such as osteonecrosis, renal and lung damage which are often clinically silent until irreversible damage has occurred. Genotype-phenotype association studies are useful in identifying novel genetic modifiers. Additionally, whole genome and exome sequencing could identify novel variants and add to our understanding of the genetic modifiers of this disease. This protocol will allow the development of a biorepository of samples and clinical data from patients with SCD receiving medical care at Childrens National Health System (CNHS) and the National Institutes of Health (NIH). Utilizing this database we will determine to what extent current genetic markers (single nucleotide polymorphisms, SNPs) can predict the clinical phenotypes and disease severity in subjects with sickle cell SCD. We also propose to derive new genetic markers using whole genome-wide association studies (GWAS) utilizing whole genome scan, whole genome sequencing (WGS) and whole exome sequencing. The information collected collaboratively will be useful in assessing clinical needs of this population as well as developing research projects for better understanding of the disease which could lead to development of novel therapies and improving outcomes for individuals living with SCD. The protocol is actively accruing patients from the NIH clinical center. Currently, 85 new patients in 2017 have been evaluated under the natural history protocol. To date a total of 631 patients enrolled. 45 subjects enrolled during for the last CR and 11 new enrollments since CR.